2-Hydroxymethylmorpholine is widely used as an intermediate for pharmaceutical products, agricultural chemicals and the like, for example, a synthetic intermediate for CNS compounds such as reboxetine, which is an antidepressant, and the like.
The following method is known as a production method of 2-hydroxymethylmorpholine.
By reacting epichlorohydrin with N-benzylethanolamine, N-benzyl-2-(hydroxymethyl)morpholine containing a 1,4-oxazepane compound is obtained. Then, this is reacted with succinic anhydride at −25° C., and the crude product is extracted with aqueous ammonia to give a hemisuccinate compound of N-benzyl-2-(hydroxymethyl)morpholine. This is further hydrolyzed with aqueous sodium hydroxide solution and extracted with an organic solvent to give N-benzyl-2-(hydroxymethyl)morpholine, which is subjected to a hydrogenation reaction using a palladium catalyst to perform debenzylation, whereby 2-hydroxymethylmorpholine is obtained (non-patent document 1).
However, in the above-mentioned method, removal of impurity (1,4-oxazepane compound) is achieved by once reacting succinic anhydride with N-benzyl-2-(hydroxymethyl)morpholine to lead to a hemisuccinate compound, performing a partitioning treatment, removing the impurity and hydrolyzing the hemisuccinate compound by an alkali treatment. As a result, the reaction steps are extremely long, and therefore, the method is complicated and impractical for industrial scale. In addition, since large amounts of aqueous ammonia and organic solvents are used to remove the impurity (1,4-oxazepane compound), the method is costly and low in efficiency. Furthermore, the reaction with succinic anhydride requires an industrially special low temperature facility to set to −25° C., and the method is not industrially suitable.
In addition, since 2-hydroxymethylmorpholine is a tacky gummy substance (non-patent document 1) which is difficult to handle, distribution thereof as an industrial product is difficult.
Patent document 1 describes that racemic 2-hydroxymethylmorpholine trifluoroacetate, which is a synthetic intermediate for pharmaceutical products, is obtained as a tacky oily substance.
Patent documents 2 and 3 describe that racemic 2-hydroxymethylmorpholine hydrochloride is obtained as a synthetic intermediate for pharmaceutical products. However, the properties thereof are not described.
These documents do not describe an optically active 2-hydroxymethylmorpholine salt.